Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X3/P2X2/3 antagonist for the treatment of pain

被引：53

作者：

Carter, David S. ^{[1
]}

Alam, Muzaffar ^{[1
]}

Cai, Haiying ^{[1
]}

Dillon, Michael P. ^{[1
]}

Ford, Anthony P. D. W. ^{[2
]}

Gever, Joel R. ^{[2
]}

Jahangir, Alam ^{[1
]}

Lin, Clara ^{[1
]}

Moore, Amy G. ^{[1
]}

Wagner, Paul J. ^{[1
]}

Zhai, Yansheng ^{[1
]}

机构：

[1] Roche Palo Alto LLC, Dept Med Chem, Palo Alto, CA 94304 USA

[2] Roche Palo Alto LLC, Dept Biochem Pharmacol, Palo Alto, CA 94304 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 06期

关键词：

P2X3; Purinoceptors; ATP; RO-4; Chronic pain; Inflammatory pain; Neuropathic pain; Drug-like; antagonist; P2X(2/3) RECEPTORS; NEUROPATHIC PAIN; SENSORY NEURONS; P2X(3); POTENT; ACCEPTORS; CHANNELS; A-317491; RATS;

D O I：

10.1016/j.bmcl.2009.02.003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X(3) and P2X(2/3) receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X(3)/P2X(2/3) antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X(3)/P2X(2/3) antagonist. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1628 / 1631

页数：4

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